Formation of intranuclear crystalloids and proliferation of the smooth endoplasmic reticulum in Schwann cells induced by tellurium treatment: Association with overexpression of HMG CoA reductase and HMG CoA synthase mRNA

Administration of tellurium (Te) in weaning rats causes a well established demyelinating neuropathy induced by the inhibition in myelinating Schwann c ells (SC) of the synthesis of cholesterol, a major component of the myelin sheath, at the level of squalene epoxidase. We have used this experimental model of Te neuropathy to study the biogenesis and reorganization of the en domembranes of the nuclear envelope and endoplasmic reticulum (ER) in respo nse to Te treatment by ultrastructural analysis and in situ hybridization f or the detection of HMG CoA reductase and synthase mRNA, which encode key e nzymes in cholesterol synthesis. The adaptive response of myelinating SC to cholesterol depletion includes cell hypertrophy, the formation of tubular invaginations of proliferating nuclear membranes giving rise to peculiar nu clear inclusions termed crystalloids, and, at the cytoplasmic level, the fo rmation of lamellar bodies of rough ER, proliferation of the smooth ER, and overexpression of HMG CoA reductase and synthase mRNAs. The changes revert after withdrawal of Te treatment. Our results show that the biogenesis and structural organization of both endomembrane systems change dynamically up on Te-induced cholesterol depletion, indicating that this constituent plays a critical role in the organization of nuclear envelope and ER compartment s in SC. The results also suggest that the HMG CoAreductase, an integral me mbrane protein of ER, provides the signal for the extensive membrane assemb ly. While the physiological meaning of crystalloid remains to be clarified, the hypertrophy of the smooth ER may represent a cytoprotective mechanism involved in detoxification of the neurotoxic agent or its metabolic derivat es. (C) 2000 Wiley-Liss, Inc.